The broad objective of this proposal is to investigate the role of interleukin-1 (IL1) in the regulation of sleep/wake cycles. We hypothesize that IL1 plays a key role in the physiological regulation of sleep. Major evidence in support of this hypothesis includes: 1) IL1 and many substances that induce IL1 production enhance non-rapid-eye-movement sleep (NREMS), 2) substances that inhibit IL1 production or activity inhibit NREMS, 3) IL1B-mRNA and IL1 receptors are found in the normal brain, 4) IL1 immunoreactive hypothalamic neurons are in the normal brain, and 5) cerebrospinal fluid levels of IL1 are higher during NREMS than during wakefulness. Despite this recent knowledge, there remains a clear need to determine sleep-related molecular mechanisms of IL1 somnogenic actions. To address these issues, using rabbit and rat sleep assay models, we propose to: Investigate substances that are know to: a) mimic IL1, e.g. IL1 fragments; and b) alter IL1 activity and/or production, e.g. anti IL1 antibodies and anti IL1-receptor antibodies; such studies will help determine what part of the iL1 molecule is responsible for this somnogenic actions, provide experimental tools that later can be used in other sleep studies and reaffirm in two species often used in sleep research that IL1, indeed, enhances NREMS. We will also investigate a positive and a negative feedback loop involved in IL1 regulation. Substances to be investigated that form part of these feedback loops include interferon and the corticotropin-releasing factor-glucocorticoid axis. Using antibodies or surgical procedures, both feedback loops will be disrupted; the effects of opening these loops on sleep and on IL1 dose-response curves will be determined. Expected results will establish a role for IL1 in sleep regulation and provide information concerning the molecular events and their order, involved in IL1-altered sleep. Such information will help provide us with an understanding of one of the major enigmas of neurobiology, the function of sleep. It will also help us understand the adaptive role sleep may play in infectious disease and possibly help guide the development of new, safe somnogenic agents.